Encapsulated tiotropium containing powder formulation for inhalation

ABSTRACT

The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use in preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 10/718,404, filed Nov.20, 2003 now U.S. Pat. No. 7,763,280. Benefit of U.S. ProvisionalApplication Ser. No. 60/446,669, filed on Feb. 11, 2003 is herebyclaimed.

FIELD OF THE INVENTION

The invention relates to powdered preparations containing tiotropium forinhalation, processes for preparing them as well as their use forpreparing a pharmaceutical composition for treating respiratorycomplaints, particularly for treating COPD (chronic obstructivepulmonary disease) and asthma.

BACKGROUND TO THE INVENTION

Tiotropium bromide is known from European Patent Application EP 418 716A1 and has the following chemical structure:

Tiotropium bromide is a highly effective anticholinergic with along-lasting activity which can be used to treat respiratory complaints,particularly COPD (chronic obstructive pulmonary disease) and asthma.The term tiotropium refers to the free ammonium cation.

For treating the abovementioned complaints, it is useful to administerthe active substance by inhalation. In addition to the administration ofbroncholytically active compounds in the form of metered aerosols andinhalable solutions, the use of inhalable powders containing activesubstance is of particular importance.

With active substances which have a particularly high efficacy, onlysmall amounts of the active substance are needed per single dose toachieve the desired therapeutic effect. In such cases, the activesubstance has to be diluted with suitable excipients in order to preparethe inhalable powder. Because of the large amount of excipient, theproperties of the inhalable powder are critically influenced by thechoice of excipient. When choosing the excipient its particle size isparticularly important. As a rule, the finer the excipient, the poorerits flow properties. However, good flow properties are a prerequisitefor highly accurate metering when packing and dividing up the individualdoses of preparation, e.g. when producing capsules (inhalettes) forpowder inhalation or when the patient is metering the individual dosebefore using a multi-dose inhaler. Moreover, the particle size of theexcipient is very important for the emptying characteristics of capsuleswhen used in an inhaler. It has also been found that the particle sizeof the excipient has a considerable influence on the proportion ofactive substance in the inhalable powder which is delivered forinhalation. The term inhalable proportion of active substance refers tothe particles of the inhalable powder which are conveyed deep into thebranches of the lungs when inhaled with a breath. The particle sizerequired for this is between 1 and 10 Mm, preferably less than 6 μm.

The aim of the invention is to prepare an inhalable powder containingtiotropium which, while being accurately metered (in terms of the amountof active substance and powder mixture packed into each capsule by themanufacturer as well as the quantity of active substance released anddelivered to the lungs from each capsule by the inhalation process) withonly slight variations between batches, enables the active substance tobe administered in a large inhalable proportion. A further aim of thepresent invention is to prepare an inhalable powder containingtiotropium which ensures good emptying characteristics of the capsules,whether it is administered to the patient using an inhaler, for example,as described in WO 94/28958, or in vitro using an impactor or impinger.

The fact that tiotropium, particularly tiotropium bromide, has atherapeutic efficacy even at very low doses imposes further conditionson an inhalable powder which is to be used with highly accuratemetering. Because only a low concentration of the active substance isneeded in the inhalable powder to achieve the therapeutic effect, a highdegree of homogeneity of the powder mixture and only slight fluctuationsin the dispersion characteristics from one batch of capsules to the nextare essential. The homogeneity of the powder mixture and minorfluctuations in the dispersion properties are crucial in ensuring thatthe inhalable proportion of active substance is released reproducibly inconstant amounts and with the lowest possible variability.

Accordingly, a further aim of the present invention is to prepare aninhalable powder containing tiotropium which is characterised by a highdegree of homogeneity and uniformity of dispersion. The presentinvention also sets out to provide an inhalable powder which allows theinhalable proportion of active substance to be administered with thelowest possible variability.

Inhalable powders containing tiotropium which conform to therequirements listed above are known for example from WO 02/30389. Theseinhalable powders are essentially characterised in that they contain inaddition to the active substance tiotropium in the form of one of thepharmacologically acceptable salts formed from tiotropium an excipientwhich is obtained by mixing coarser excipient fractions with finerexcipienty fractions. However, technically complex manufacturing andmixing methods are required in order to prepare these inhalable powdersknown from WO 02/30389. A further aim of the present invention istherefore to provide inhalable powders which not only solve the problemsmentioned above but can also be obtained by an easier technical methodof preparation.

The characteristics of emptying from the powder reservoir (the containerfrom which the inhalable powder containing the active substance isreleased for inhalation) play an important part, not exclusively, butespecially in the administration of inhalable powders using capsulescontaining powder. If only a small amount of the powder formulation isreleased from the powder reservoir as a result of minimal or pooremptying characteristics, significant amounts of the inhalable powdercontaining the active substance are left in the powder reservoir (e.g.the capsule) and are unavailable to the patient for therapeutic use. Theresult of this is that the dosage of active substance in the powdermixture has to be increased so that the quantity of active substancedelivered is sufficient to produce the desired therapeutic effect.

Against this background the present invention further sets out toprovide an inhalable powder which is also characterised by very goodemptying characteristics.

DETAILED DESCRIPTION OF THE INVENTION

It was found that, surprisingly, the objectives outlined above can beachieved by means of the powdered preparations for inhalation (inhalablepowders) according to the invention described hereinafter.

Accordingly, the present invention relates to inhalable powderscontaining 0.001 to 3% of tiotropium mixed with a physiologicallyacceptable excipient, characterised in that the excipient has an averageparticle size of 10-50 μm, a 10% fine content of 0.5 to 6 μm and aspecific surface area of 0.1 to 2 m²/g.

By the average particle size is meant here the 50% value of the volumedistribution measured using a laser diffractometer by the dry dispersionmethod. Analogously, the 10% fine content in this instance refers to the10% value of the volume distribution measured using a laserdiffractometer. In other words, for the purposes of the presentinvention, the 10% fine content denotes the particle size below which10% of the quantity of particles is found (based on the volumedistribution).

By specific surface area is meant, for the purposes of the invention,the mass-specific powder surface area, calculated from the N₂ absorptionisotherm which is observed at the boiling point of liquid nitrogen(method of Brunauer, Emmett and Teller).

Inhalable powders which contain 0.01 to 2% of tiotropium are preferredaccording to the invention. Particularly preferred inhalable powderscontain tiotropium in an amount of about 0.03 to 1%, preferably 0.05 to0.6%, more preferably 0.06 to 0.3%. Of particular importance accordingto the invention are, finally, inhalable powders which contain about0.08 to 0.22% tiotropium.

By tiotropium is meant the free ammonium cation. Where the term activesubstance is used within the scope of the present invention, this shouldbe interpreted as being a reference to tiotropium combined with acorresponding counter-ion. The counter-ion (anion) may preferably bechloride, bromide, iodide, methanesulphonate or para-toluenesulphonate.Of these anions, the bromide is preferred.

Accordingly, the present invention preferably relates to inhalablepowders which contain between 0.0012 and 3.6%, preferably 0.012 to 2.4%tiotropium bromide. Of particular interest according to the inventionare inhalable powders which contain about 0.036 to 1.2%, preferably 0.06to 0.72%, more preferably 0.072 to 0.36% tiotropium bromide. Ofparticular interest according to the invention are inhalable powderswhich contain about 0.096 to 0.264% tiotropium bromide.

The tiotropium bromide which is preferably contained in the inhalablepowders according to the invention may include solvent molecules duringcrystallisation. Preferably, the hydrates of tiotropium bromide are usedto prepare the tiotropium-containing inhalable powder according to theinvention. Most preferably, the crystalline tiotropium bromidemonohydrate known from WO 02/30928 is used. This crystalline tiotropiumbromide monohydrate is characterised by an endothermic maximum at 230±5°C. at a heating rate of 10K/min, when thermally analysed by DSC. It isalso characterised in that in the IR spectrum it has bands inter alia atwavelengths 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm⁻¹. Finally,this crystalline tiotropium bromide monohydrate has a simple monocliniccell with the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321Å, β=102.691°, V=2096.96 Å³ as determined by monocrystalline X-raystructural analysis.

Accordingly the present invention relates to powders for inhalationwhich contain between 0.0013 and 3.75%, preferably 0.0125 to 2.5% oftiotropium bromide monohydrate. Of particular interest according to theinvention are inhalable powders which contain about 0.0375 to 1.25%,preferably 0.0625 to 0.75%, more preferably 0.075 to 0.375% oftiotropium bromide monohydrate. Finally, of particular importanceaccording to the invention are inhalable powders which contain about 0.1to 0.275% tiotropium bromide monohydrate.

The percentages given within the scope of the present invention arealways percent by weight, unless specifically stated to the contrary.

In particularly preferred inhalable powders the excipient ischaracterised by an average particle size of 12 to 35 μm, morepreferably 13 to 30 μm. Also particularly preferred are those inhalablepowders wherein the 10% fine content is about 1 to 4 μm, preferablyabout 1.5 to 3 μm.

Also preferred according to the invention are those inhalable powderswherein the excipient has a specific surface area of between 0.2 and 1.5m²/g, preferably between 0.3 and 1.0 m²/g.

The excipients which are used for the purposes of the present inventionare prepared by suitable milling and/or screening using conventionalmethods known in the art. In particular, the excipients used accordingto the invention are not mixtures of excipients obtained by mixingtogether excipient fractions with different average particle sizes.

Examples of physiologically acceptable excipients which may be used toprepare the inhalable powders used for the inhalettes according to theinvention include, for example, monosaccharides (e.g. glucose orarabinose), disaccharides (e.g. lactose, saccharose, maltose,trehalose), oligo- and polysaccharides (e.g. dextrane), polyalcohols(e.g. sorbitol, mannitol, xylitol), or salts (e.g. sodium chloride,calcium carbonate). Preferably, mono- or disaccharides are used, whilethe use of lactose or glucose is preferred, particularly, but notexclusively, in the form of their hydrates. For the purposes of theinvention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Preferably, excipients of high crystallinity are used for the powderformulations according to the invention. This crystallinity can beassessed by means of the enthalpy released as the excipient is dissolved(solution enthalpy). In the case of the excipient lactose monohydrate,which is most preferably used according to the invention, it ispreferable to use lactose which is characterised by a solution enthalpyof ≧45 J/g, preferably ≧50 J/g, particularly preferably ≧52 J/g.

The inhalable powders according to the invention are characterised, inaccordance with the problem on which the invention is based, by a highdegree of homogeneity in the sense of the accuracy of single doses. Thisis in the region of <8%, preferably <6%, most preferably <4%.

After the starting materials have been weighed in the inhalable powdersare prepared from the excipient and the active substance using methodsknown in the art. Reference may be made to the disclosure of WO02/30390, for example. The inhalable powders according to the inventionmay accordingly be obtained by the method described below, for example.In the preparation methods described hereinafter the components are usedin the proportions by weight described in the above-mentionedcompositions of the inhalable powders.

First, the excipient and the active substance are placed in a suitablemixing container. The active substance used has an average particle sizeof 0.5 to 10 μm, preferably 1 to 6 μm, most preferably 2 to 5 μm. Theexcipient and the active substance are preferably added using a sieve ora granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1mm, most preferably 0.3 to 0.6 mm. Preferably, the excipient is put infirst and then the active substance is added to the mixing container.During this mixing process the two components are preferably added inbatches. It is particularly preferred to sieve in the two components inalternate layers. The mixing of the excipient with the active substancemay take place while the two components are still being added.Preferably, however, mixing is only done once the two components havebeen sieved in layer by layer.

If after being chemically prepared the active substance used in theprocess described above is not already obtainable in a crystalline formwith the particle sizes mentioned earlier, it can be ground up into theparticle sizes which conform to the above-mentioned parameters(so-called micronising).

If the active substance used is the crystalline tiotropium bromidemonohydrate disclosed by WO 02/30928 which is particularly preferredaccording to the invention the following procedure has provedparticularly suitable for micronising this crystalline active substancemodification. The process may be carried out using conventional mills.Preferably, the micronisation is carried out with the exclusion ofmoisture, more preferably, using a corresponding inert gas such asnitrogen, for example. It has proved particularly preferable to use airjet mills in which the material is comminuted by the impact of theparticles on one another and on the walls of the grinding container.According to the invention, nitrogen is preferably used as the grindinggas. The material for grinding is conveyed by the grinding gas underspecific pressures (grinding pressure). Within the scope of the presentinvention, the grinding pressure is usually set to a value between about2 and 8 bar, preferably between about 3 and 7 bar, most preferablybetween about 3.5 and 6.5 bar. The material for grinding is fed into theair jet mill by means of the feed gas under specific pressures (feedpressure). Within the scope of the present invention a feed pressure ofbetween about 2 and 8 bar, preferably between about 3 and 7 bar and mostpreferably between about 3.5 and 6 bar has proved satisfactory. The feedgas used is also preferably an inert gas, most preferably nitrogenagain. The material to be ground (crystalline tiotropium bromidemonohydrate) may be fed in at a rate of about 5-35 g/min, preferably atabout 10-30 g/min.

For example, without restricting the subject of the invention thereto,the following apparatus has proved suitable as a possible embodiment ofan air jet mill: a 2-inch Microniser with grinding ring, 0.8 mm bore,made by Messrs Sturtevant Inc., 348 Circuit Street, Hanover, Mass.02239, USA. Using the apparatus, the grinding process is preferablycarried out with the following grinding parameters: grinding pressure:about 4.5-6.5 bar; feed pressure: about 4.5-6.5 bar; supply of grindingmaterial: about 17-21 g/min.

The ground material thus obtained is then further processed under thefollowing specific conditions. The micronisate is exposed to a watervapour at a relative humidity of at least 40% at a temperature of 15-40°C., preferably 20-35° C., most preferably 25-30° C. Preferably, thehumidity is set to a value of 50-95% r. h., preferably 60-90% r.h., mostpreferably 70-80% r.h. By relative humidity (r.h.) is meant the quotientof the partial steam pressure and the steam pressure of the water at thetemperature in question. Preferably, the micronisate obtained from thegrinding process described above is subjected to the chamber conditionsmentioned above for a period of at least 6 hours. Preferably, however,the micronisate is subjected to the chamber conditions mentioned abovefor about 12 to 48 hours, preferably about 18 to 36 hours, morepreferably about 20 to 28 hours.

The micronisate of tiotropium bromide obtainable by the above method hasa characteristic particle size of between 1.0 μm and 3.5 μm, preferablybetween 1.1 μm and 3.3 μm, most preferably between 1.2 μm and 3.0 μm andQ_((5.8)) of more than 60%, preferably more than 70%, most preferablymore than 80%. The characteristic value Q_((5.8)) indicates the quantityof particles below 5.8 μm, based on the volume distribution of theparticles. The particle sizes were determined within the scope of thepresent invention by laser diffraction (Fraunhofer diffraction). Moredetailed information on this subject can be found in the experimentaldescriptions of the invention.

Also characteristic of the tiotropium micronisate according to theinvention which was prepared by the above process are Specific SurfaceArea values in the range between 2 m²/g and 5 m²/g, more particularlybetween 2.5 m²/g and 4.5 m²/g and most outstandingly between 3.0 m²/gand 4.0 m²/g.

A particularly preferred aspect of the present invention relates to theinhalable powders according to the invention which are characterised bya content of the tiotropium bromide monohydrate micronisate describedhereinbefore.

The present invention further relates to the use of the inhalablepowders according to the invention for preparing a pharmaceuticalcomposition for the treatment of respiratory diseases, particularly fortreating COPD and/or asthma.

The inhalable powders according to the invention may for example beadministered using inhalers which meter a single dose from a reservoirby means of a measuring chamber (e.g. according to U.S. Pat. No.4,570,630A) or by other means (e.g. according to DE 36 25 685 A).Preferably, however, the inhalable powders according to the inventionare packed into capsules (to make so-called inhalettes), which are usedin inhalers such as those described in WO 94/28958, for example.

Most preferably, the capsules containing the inhalable powder accordingto the invention are administered using an inhaler as shown in FIG. 1.This inhaler is characterised by a housing 1 containing two windows 2, adeck 3 in which there are air inlet ports and which is provided with ascreen 5 secured via a screen housing 4, an inhalation chamber 6connected to the deck 3 on which there is a push button 9 provided withtwo sharpened pins 7 and movable counter to a spring 8, and a mouthpiece12 which is connected to the housing 1, the deck 3 and a cover 11 via aspindle 10 to enable it to be flipped open or shut and airholes 13 foradjusting the flow resistance.

The present invention further relates to the use of the inhalablepowders according to the invention for preparing a pharmaceuticalcomposition for treating respiratory complaints, particularly for thetreatment of COPD and/or asthma, characterised in that the inhalerdescribed above and shown in FIG. 1 is used.

For administering the inhalable powders according to the invention usingpowder-filled capsules it is particularly preferred to use capsules thematerial of which is selected from among the synthetic plastics, mostpreferably selected from among polyethylene, polycarbonate, polyester,polypropylene and polyethylene terephthalate. Particularly preferredsynthetic plastic materials are polyethylene, polycarbonate orpolyethylene terephthalate. If polyethylene is used as one of thecapsule materials which is particularly preferred according to theinvention, it is preferable to use polyethylene with a density ofbetween 900 and 1000 kg/m³, preferably 940-980 kg/m³, more preferablyabout 960-970 kg/m³ (high density polyethylene).

The synthetic plastics according to the invention may be processed invarious ways using manufacturing methods known in the art. Injectionmoulding of the plastics is preferred according to the invention.Injection moulding without the use of mould release agents isparticularly preferred. This method of production is well defined and ischaracterised by being particularly reproducible.

In another aspect the present invention relates to the abovementionedcapsules which contain the abovementioned inhalable powders according tothe invention. These capsules may contain about 1 to 20 mg, preferablyabout 3 to 15 mg, most preferably about 4 to 12 mg of inhalable powder.Preferred formulations according to the invention contain 4 to 6 mg ofinhalable powder. Of equivalent importance according to the inventionare capsules for inhalation which contain the formulations according tothe invention in an amount of from 8 to 12 mg.

The present invention also relates to an inhalation kit consisting ofone or more of the above capsules characterised by a content ofinhalable powder according to the invention in conjunction with theinhaler according to FIG. 1.

The present invention also relates to the use of the abovementionedcapsules characterised by a content of inhalable powder according to theinvention, for preparing a pharmaceutical composition for treatingrespiratory complaints, especially for treating COPD and/or asthma.

Filled capsules which contain the inhalable powders according to theinvention are produced by methods known in the art, by filling the emptycapsules with the inhalable powders according to the invention.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows an example of an inhaler useful for administering thecapsules containing the inhalable powder according to the invention.

EXAMPLES

The following Examples serve to illustrate the present invention in moredetail without restricting the scope of the invention to theexemplifying embodiments that follow.

Starting Materials

I) Excipient:

In the Examples that follow lactose-monohydrate is used as excipient. Itmay be obtained for example from Borculo Domo Ingredients, Borculo/NLunder the product name Lactochem Extra Fine Powder. The specificationsaccording to the invention for the particle size and specific surfacearea are met by this grade of lactose. In addition, this lactose has theabove-mentioned preferred solution enthalpy values for lactose accordingto the invention.

II) Micronisation of Crystalline Tiotropium Bromide Monohydrate:

The tiotropium bromide monohydrate obtainable according to WO 02/30928is micronised with an air jet mill of the 2-inch microniser type withgrinding ring, 0.8 mm bore, made by Messrs Sturtevant Inc., 348 CircuitStreet, Hanover, Mass. 02239, USA. Using nitrogen as the grinding gasthe following grinding parameters are set, for example:

grinding pressure: 5.5 bar; feed pressure: 5.5 bar; supply (ofcrystalline monohydrate) or flow speed: 19 g/min.

The ground material obtained is then spread out on sheet metal racks ina layer thickness of about 1 cm and subjected to the following climaticconditions for 24-24.5 hours:

temperature: 25-30° C.; relative humidity: 70-80%.

Measuring Methods:

Determining the Particle Size of Micronised Tiotropium Monohydrate:

Measuring Equipment and Settings:

The equipment is operated according to the manufacturer's instructions.

Measuring equipment: HELOS Laser-diffraction spectrometer, (SympaTec)Dispersing unit: RODOS dry disperser with suction funnel, (SympaTec)Sample quantity: 200 mg ± 150 mg Product feed: Vibri Vibrating channel,Messrs. Sympatec Frequency of vibrating rising to 100% channel: Durationof sample feed: 15 to 25 sec. (in the case of 200 mg) Focal length: 100mm (measuring range: 0.9-175 μm) Measuring time: about 15 s (in the caseof 200 mg) Cycle time: 20 ms Start/stop at: 1% on channel 28 Dispersinggas: compressed air Pressure: 3 bar Vacuum: maximum Evaluation method:HRLDSample Preparation/Product Feed:

About 200 mg of the test substance are weighed onto a piece of card.

Using another piece of card all the larger lumps are broken up. Thepowder is then sprinkled finely over the front half of the vibratingchannel (starting about 1 cm from the front edge). After the start ofthe measurement the frequency of the vibrating channel is varied so thatthe sample is fed in as continuously as possible. However, the quantityof product should not be too great either, so as to ensure adequatedispersal.

II) Determining the Particle Size of the Lactose:

Measuring Equipment and Settings:

The equipment is operated according to the manufacturer's instructions.

Measuring equipment: HELOS Laser-diffraction spectrometer, (SympaTec)Dispersing unit: RODOS dry disperser with suction funnel, (SympaTec)Sample quantity: 200 mg ± 100 mg Product feed: Vibri Vibrating channel,Messrs. Sympatec Frequency of vibrating 100% rising channel: Focallength: 200 mm (measuring range: 1.8-350 μm) Measuring time: about 10 s(in the case of 200 mg) Cycle time: 10 ms Start/stop at: 1% on channel28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximumEvaluation method: HRLDSample Preparation/Product Feed:

About 200 mg of the test substance are weighed onto a piece of card.

Using another piece of card all the larger lumps are broken up. Thepowder is transferred into the vibrating channel. A gap of 1.2 to 1.4 mmis set between the vibrating channel and funnel. After the start of themeasurement the frequency of the vibrating channel is increased ascontinuously as possible to 100% towards the end of the measurement.

III) Determining the Specific Surface Area of Tiotropium BromideMonohydrate, Micronised (1-Point BET Method):

Method:

The specific surface is determined by exposing the powder sample to anitrogen/helium atmosphere at different pressures. Cooling the samplecauses the nitrogen molecules to be condensed on the surface of theparticles. The quantity of condensed nitrogen is determined by means ofthe change in the thermal heat conductivity of the nitrogen/heliummixture and the surface of the sample is calculated by means of thesurface nitrogen requirement. Using this value and the weight of thesample, the specific surface is calculated.

Equipment and Materials:

Measuring equipment: Monosorb, Messrs Quantachrome Heater: Monotektor,Messrs Quantachrome Measuring and nitrogen (5.0)/helium (4.6) 70/30,Messer drying gas: Griesheim Adsorbate: 30% nitrogen in helium Coolant:liquid nitrogen Measuring cell: with capillary tube, Messrs. W. PabischGmbH&Co.KG Calibration peak; 1000 μl, Messrs. Precision Sampling Corp.Analytical scale: R 160 P, Messrs. SatoriusCalculating the Specific Surface:

The measured values are indicated by the equipment in [m²] and areusually converted into [cm²/g] on weighing (dry mass):

$A_{spez} = \frac{{MW}*10000}{m_{tr}}$A_(spez) = specific  surface  [cm²/g] MW = Measured  value  [m²]m_(tr) = dry  mass  [g] 10000 = conversion   factor  [cm²/m²] IV)_Determining the Specific Surface Area of the Lactose (Multi-PointBet Method):Method:

The specific surface is determined by exposing the powder sample to anitrogen atmosphere at different pressures. Cooling the sample causesthe nitrogen molecules to be condensed on the surface of the particles.The quantity of condensed nitrogen is determined by means of the drop inpressure in the system and the specific surface of the sample iscalculated by means of the surface nitrogen requirement and the weightof the sample.

The equipment is operated according to the manufacturer's instructions.

Measuring Equipment and Settings:

Measuring equipment Tri Star Multi Point BET, Messrs MicromeriticsHeater: VacPrep 061, Messrs. Micromeritics Heating: about 12 h/40° C.Sample tube: ½ inch; use filler rod Analysis Condition: 10 point BETsurface 0.1 to 0.20 p/p0 Absolute P. tolerance: 5.0 mmHg rel. P.tolerance: 5.0% Evacuation rate: 50.0 mmHg/sec. Unrestricted evac f.:10.0 mmHg Evac. time: 0.1 hours Free Space: Lower Dewar, time: 0.5 hEquilibration interv.: 20 sec Min. equl. delay: 600 sec Adsorptive:NitrogenV) Determining the Heat of Solution (Enthalpy of Solution) E_(c):

The solution enthalpy is determined using a solution calorimeter 2225Precision Solution Calorimeter made by Messrs. Thermometric.

The heat of solution is calculated by means of the change in temperatureoccurring (as a result of the dissolving process) and the system-relatedchange in temperature calculated from the base line.

Before and after the ampoule is broken, electrical calibration iscarried out with an integrated heating resistor of a precisely knownpower. A known heat output is delivered to the system over a set periodand the jump in temperature is determined.

Method and Equipment Parameters:

Solution calorimeter: 2225 Precision Solution Calorimeter, MessrsThermometric Reaction cell: 100 ml Thermistor resistance: 30.0 kΩ (at25° C.) Speed of stirrer: 500 U/min Thermostat: Thermostat of 2277Thermal Activity Monitor TAM, Messrs Thermometric Temperature: 25° C. ±0.0001° C. (over 24 h) Measuring ampoules: Crushing ampoules 1 ml,Messrs Thermometric Seal: Silicon stopper and beeswax, Messrs.Thermometric Weight: 40 to 50 mg Solvent: Chemically pure water Volumeof solvent: 100 ml Bath temperature: 25° C. Temperature resolution: HighStarting temperature: −40 mK (±10 mK) temperature-offset Interface:2280-002 TAM accessory interface 50 Hz, Messrs Thermometric Software:SolCal V 1.1 for WINDOWS Evaluation: Automatic evaluation with Menupoint CALCULATION/ANALYSE EXPERIMENT. (Dynamics of base line;calibration after breakage of ampoule).Electrical Calibration:

The electrical calibration takes place during the measurement, oncebefore and once after the breakage of the ampoule. The calibration afterthe breakage of the ampoule is used for the evaluation.

Amount of heat: 2.5 J Heating power: 500 mW Heating time: 10 s Durationof base lines: 5 min (before and after heating)Preparation of the Powder Formulations According to the Invention:I) Apparatus

The following machines and equipment, for example, may be used toprepare the inhalable powders:

Mixing container or powder mixer: Turbulamischer 2 L, Type 2C; made byWilly A. Bachofen AG, CH-4500 Basel

Hand-held screen: 0.135 mm mesh size

The empty inhalation capsules may be filled with inhalable powderscontaining tiotropium by hand or mechanically. The following equipmentmay be used.

Capsule Filling Machine:

MG2, Type G100, manufacturer: MG2 S.r.l, I-40065 Pian di Macina diPianoro (BO), Italy

Example 1 Powder Mixture

To prepare the powder mixture, 299.39 g of excipient and 0.61 g ofmicronised tiotropium bromide-monohydrate are used. In the resulting 300g of inhalable powder the content of active substance is 0.2% (based ontiotropium).

About 40-45 g of excipient are placed in a suitable mixing containerthrough a hand-held screen with a mesh size of 0.315 mm. Then tiotropiumbromide-monohydrate in batches of about 90-110 mg and excipient inbatches of about 40-45 g are screened in in alternate layers. Theexcipient and active substance are added in 7 and 6 layers,respectively.

Having been screened in, the ingredients are then mixed (mixing speed900 rpm). The final mixture is passed twice more through a hand-heldscreen and then mixed again at 900 rpm.

Using the method described in Example 1 it is possible to obtaininhalable powders which when packed into suitable plastic capsules maybe used to produce the following capsules for inhalation, for example:

Example 2

tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate*⁾: 5.4887mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 17.9μm; 10% fine content: 2.3 μm; specific surface: 0.61 m²/g;

Example 3

tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate*⁾: 5.4887mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 18.5μm; 10% fine content: 2.2 μm; specific surface: 0.83 m²/g;

Example 4

tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate*⁾: 5.4887mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 21.6μm; 10% fine content: 2.5 μm; specific surface: 0.59 m²/g;

Example 5

tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate*⁾: 5.4887mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 16.0μm; 10% fine content: 2.0 μm; specific surface: 0.79 m²/g;

Example 6

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate*⁾: 5.4775mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 17.9μm; 10% fine content: 2.3 μm; specific surface: 0.61 m²/g;

Example 7

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate*⁾: 5.4775mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 18.5μm; 10% fine content: 2.2 μm; specific surface: 0.83 m²/g;

Example 8

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate*⁾: 5.4775mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 21.6μm; 10% fine content: 2.5 μm; specific surface: 0.59 m²/g;

Example 9

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate*⁾: 5.4775mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 16.0μm; 10% fine content: 2.0 μm; specific surface: 0.79 m²/g;

Example 10

tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate*⁾: 5.4944mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 17.9μm; 10% fine content: 2.3 μm; specific surface: 0.61 m²/g;

Example 11

tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate*⁾: 5.4944mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 18.5μm; 10% fine content: 2.2 μm; specific surface: 0.83 m²/g;

Example 12

tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate*⁾: 5.4944mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 21.6μm; 10% fine content: 2.5 μm; specific surface: 0.59 m²/g;

Example 13

tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate*⁾: 5.4944mg polyethylene capsules: 100.0 mg Total: 105.5 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 16.0μm; 10% fine content: 2.0 μm; specific surface: 0.79 m²/g;

Example 14

tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate*⁾: 9.9944mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 17.9μm; 10% fine content: 2.3 μm; specific surface: 0.61 m²/g;

Example 15

tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate*⁾: 9.9887mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 18.5μm; 10% fine content: 2.2 μm; specific surface: 0.83 m²/g;

Example 16

tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate*⁾: 9.9775mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 21.6μm; 10% fine content: 2.5 μm; specific surface: 0.59 m²/g;

Example 17

tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate*⁾: 9.9875mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 17.9μm; 10% fine content: 2.3 μm; specific surface: 0.61 m²/g;

Example 18

tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate*⁾: 9.9875mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 18.5μm; 10% fine content: 2.2 μm; specific surface: 0.83 m²/g;

Example 19

tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate*⁾: 9.9875mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 21.6μm; 10% fine content: 2.5 μm; specific surface: 0.59 m²/g;

Example 20

tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate*⁾: 9.9875mg polyethylene capsules: 100.0 mg Total: 110.0 mg *⁾the excipient ischaracterised by the following parameters: average particle size: 16.0μm; 10% fine content: 2.0 μm; specific surface: 0.79 m²/g;

1. A capsule containing an inhalable powder, wherein the capsuleconsists essentially of one or more synthetic plastics and the inhalablepowder composition comprises 0.001 to 3% of tiotropium, or apharmaceutically acceptable salt thereof, in admixture with aphysiologically acceptable excipient having an average particle size of10-50 μm, a 10% fine content of 0.5 to 6 μm and a specific surface of0.1 to 2 m²/g, wherein the physiologically acceptable excipient islactose monohydrate characterized by a solution enthalpy of ≧50 J/g andwherein the synthetic plastic consists essentially of polyethylene,polycarbonate, polyester, polypropylene or polyethylene terephthalate.2. The capsule containing an inhalable powder according to claim 1,wherein the tiotropium is present as a chloride, bromide, iodide,methanesulphonate or para-toluenesulphonate salt.
 3. The capsulecontaining an inhalable powder according to claim 1, wherein the capsulecontains about 1 to 20 mg of the inhalable powder.
 4. The capsulecontaining an inhalable powder according to claim 1, wherein the capsuleis capable of use in an inhaler device to administer the inhalablepowder by inhalation.